Methylprednisolone belongs to the pharmacologic class of glucocorticoid/anti-inflammatory drugs which, following systemic absorption, diffuse across cell membranes and complex with specific cytoplasmic receptors. These complexes may enter the cell nucleus, bind to DNA and stimulate transcription of mRNA. Subsequent cellular responses result in a variety of local and systemic effects. Anti-inflammatory processes such as edema, fibrin deposition, decreased prostaglandin/thromboxane synthesis, capillary dilation, migration of leukocytes, phagocytosis stage of wound healing and cicatrization are inhibited. Immune reactions are suppressed. Metabolically, protein catabolism and increased gluconeogenesis along with decreased peripheral utilization of glucose leads to glycogen storage in the liver, increased blood glucose concentration and insulin resistance (diabetogenic effect). During therapy lipolysis is inhanced and abnormal distribution of fat may result (Cushingoid effect). Skeletal calcium is mobilized and lost via renal excretion. Glucocorticoids in general augment renal glomerular filtration and promote urate excretion.

In respect of electrolyte and water balance, sodium tends to be reabsorbed and potassium and hydrogen excreted resulting in water retention and risk of hypokalemic alkalosis.

Methylprednisolone has a greater anti-inflammatory potency than prednisolone and has less tendency than prednisolone to induce sodium and water retention.

Methylprednisolone has the same metabolic and anti-inflammatory actions as hydrocortisone. When given parenterally and in equimolar quantities, the 2 compounds are equivalent in biologic activity. The relative potency of methylprednisolone and hydrocortisone, following i.v. administration, is at least 4 to 1. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone.

A water-soluble corticosteroid salt should be administered i.v. to achieve a rapid onset of action.

Cortisone and prednisone are reduced to their pharmacologically active forms, hydrocortisone and prednisolone respectively. Pharmacologically active compounds are then metabolized primarily in the liver to biologically inactive compounds. Inactive metabolites, primarily glucuronides and sulfates are excreted by the kidneys. Small amounts of unmetabolized drug are excreted in urine and bile.

Indications And Clinical Uses: Management of conditions known to be responsive to prednisone or prednisolone where anti-inflammatory action or immunosuppression or adrenocortical supplementation and replacement is required.

For most indications, glucocorticoid administration provides symptomatic relief, but has no effect on the underlying disease process. Use of these medications does not eliminate the need for other therapies that may be required.

Situations in which a rapid and intense hormonal effect is required. These include the following:

Ulcerative Colitis: In addition to the above conditions, colonic installations of methylprednisolone for injection in retention enemas or by continuous drip have been shown to be a useful adjunct in the treatment of patients with ulcerative colitis.

Anaphylactic Reactions: Epinephrine or norepinephrine should be administered first for an immediate hemodynamic effect followed by i.v. injection of methylprednisolone and other accepted procedures. There is evidence that the corticoids through their prolonged hemodynamic effect are of value in preventing recurrent attacks of acute anaphylactic reactions.

Sensitivity Reactions: Such as in serum sickness, allergic dermatosis (urticaria) and reactions to insect bites, methylprednisolone is capable of providing relief within 0.5 to 2 hours. In some asthmatic patients it may be advantageous to administer methylprednisolone by slow i.v. drip over a period of hours.

As Adjunctive Therapy in Fulminating Acute Systemic Lupus Erythematosus and Acute Rheumatic Fever, and to Relieve Pain During the Acute Manifestations of Gout: May be given by slow i.v. administration over a period of several minutes. Thereafter, the patient should be placed on i.m. or oral therapy as required for continued relief of symptoms. In these conditions, other accepted measures of therapy should also be instituted.

Shock: In severe hemorrhagic or traumatic shock, adjunctive use of i.v. methylprednisolone may aid in achieving hemodynamic restoration. [Although there are no well-controlled (double-blind placebo) clinical trials, data from experimental animal models indicate that methylprednisolone may be useful in hemorrhagic and traumatic shock. See also Warnings regarding septic shock.] Corticoid therapy should not replace standard methods of combatting shock, but present evidence indicates that concurrent use of large doses of corticoids with other measures may improve survival rates.

Organ Transplants: Corticosteroids both parenterally and orally in high doses have been used following organ transplantation as part of multifaceted attempts to reduce the rejection phenomenon. Methylprednisolone is suitable for such indications.

Cerebral Edema: Corticosteroid therapy as an adjunct to the usual forms of therapy for cerebral edema has been used for many years. Cerebral edema associated with acute craniocerebral injuries and intracranial hematomas of traumatic origin has been treated with methylprednisolone with some improvement in overall survival rate and reduction of permanent disability following such conditions. Administration immediately prior to intracranial surgery and in the immediate postoperative period has reduced the duration of postoperative complications related to cerebral edema.

Acute Spinal Cord Injury: The use of methylprednisolone in high dose has resulted in improvement in motor and sensory recovery. Treatment should begin within 8 hours of injury.

Contra-Indications: Untreated systemic fungal infections.

Hypersensitivity to methylprednisolone, or other corticosteroids, or to any of its ingredients.

Manufacturers' Warnings In Clinical States: Glucocorticoid-induced suppression of HPA (Hypothalamic-Pituitary-Adrenal) function is dependent on dose and duration of treatment. Recovery occurs gradually as the steroid dose is reduced and withdrawn. Suppression persists for a period of time after withdrawal depending on dose and length of treatment time.

In patients on corticosteroid therapy subjected to unusual stress, increased dosage of rapidly acting corticosteroids before, during and after the stressful situation is indicated. Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.

If corticosteroids have to be used in the presence of fungal or bacterial infections, institute appropriate anti-infective therapy.

Prolonged use of corticosteroids may produce posterior subcapsular cataracts or glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses.

Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. While on corticosteroid therapy, patients should not be vaccinated against measles. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high doses, because of possible hazards of neurological complications and lack of antibody response.

The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Patients who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles can have a more serious or even fatal course in non-immune children or adults who are on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled i.m. immunoglobulin (IG) may be indicated. If chicken pox develops, treatment with antiviral agents may be considered.

Recent studies do not establish the efficacy of methylprednisolone in septic shock and suggest that increased mortality may occur in some subgroups at higher risk (i.e., elevated serum creatinine greater than 2.0 mg% or secondary infections).

Because rare instances of anaphylactoid (e.g., bronchospasm) reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of allergy to any drug.

Should bacteriostatic water for injection be used for reconstitution, note that benzyl alcohol has been reported to be associated with a fatal "Gasping syndrome" in premature infants.

Precautions: During prolonged corticosteroid therapy, routine laboratory studies such as urinalysis, 2-hour postprandial blood sugar determinations, blood pressure monitoring, body weight and chest X-ray should be performed at regular intervals. If doses of methylprednisolone are high, serum potassium should be monitored regularly. Serious consideration of upper gastrointestinal studies should be contemplated when patients complain of gastric symptoms while on this medication. Prolonged therapy above 8 mg/day is associated with doses exceeding 40 mg/day.

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or mineralocorticoids should be administered concurrently.

Children: Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Administration of corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen.

Following prolonged therapy, psychological and/or physiological dependence may develop. Withdrawal of glucocorticoids may result in symptoms of the glucocorticoid withdrawal syndrome including: fever, myalgia, arthralgia and malaise. This may occur in patients even without evidence of adrenal insufficiency.

ASA and other NSAIDs should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.

Corticosteroids Should be Used With Caution in the Following Clinical Conditions: Nonspecific ulcerative colitis (if there is a probability of impending perforation), abscess or other pyogenic infection, diverticulitis, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, cardiac disease, thromboembolic disorders and diabetes mellitus.

In myasthenia gravis, hospitalization with careful observation is recommended because transient worsening of symptoms, possibly leading to respiratory distress, may precede clinical improvement.

There are reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest following the rapid administration or large i.v. doses of methylprednisolone (greater than 0.5 g administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of methylprednisolone and may be unrelated to the speed or duration of infusion.

Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Patients should be warned not to discontinue the use of methylprednisolone abruptly or without medical supervision, to advise any medical attendants that they are taking methylprednisolone and to seek medical advice at once should they develop fever or other signs of infection.

Corticosteroids may mask some signs of infection and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used.

Adequate adrenocortical supportive therapy including ACTH must be employed promptly if the patient is subjected to any unusual stress such as surgery, trauma or severe infection.

Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay (See Warnings).

Steroids may increase or decrease motility and number of spermatozoa in some male patients. However, it is not known whether reproductive capacity in humans is adversely affected.

Carcinogenicity and Mutagenicity: There is no evidence that corticosteroids are carcinogenic.

Drug Interactions: Although no unusual drug interactions have been detected during clinical trials, the same precautions should be exercised as for other glucocorticoids. It is recommended to increase the maintenance dose of glucocorticoids if the following drugs are administered at the same time: anticonvulsants (phenobarbital, phenytoin), certain antibiotics (rifampin), anticoagulants (coumarin) and bronchodilators (ephedrine). If the patient receiving glucocorticoids is treated at the same time with some other antibiotics (erythromycin), ketoconazole, estrogens or preparations containing estrogens, a reduction in the dose of methylprednisolone is recommended. Since methylprednisolone is metabolized in the liver, the possibility remains that concomitant administration of other hepatically metabolized drugs may lead to interactions (e.g., barbiturates).

Anticholinesterase effects may be antagonized in myasthenia gravis. Toxicity may be enhanced when cyclosporin and glucocorticoids are combined in organ transplant patients. Coadministration with digitalis glycosides may enhance the possibility of digitalis toxicity associated with hypocalcemia. Isoniazid and salicylate serum concentrations may be decreased upon coadministration with glucocorticoids.

Potassium-depleting agents (e.g., thiazide diuretics) may enhance hypocalcemia and hypokalemia secondary to glucocorticoid use. Coadministration with nonsteroidal anti-inflammatories may increase the risk of gastrointestinal ulceration. Immunologic response to vaccines and toxoids is reduced by glucocorticoids which may also potentiate the replication of organisms in attenuated vaccines (e.g., measles). Glucocorticoids may alter laboratory or radiological tests for serum T3 or serum protein-bound iodine, may decrease T4 minimally or decrease the uptake of 31odine.

Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy (e.g., Addison's disease).

Convulsions have been reported with concurrent use of methylprednisolone and cyclosporine. Since concurrent administration of these agents results in a mutual inhibition of metabolism, it is possible that convulsions and other adverse events associated with the individual use of either drug may be more apt to occur.

Pregnancy: Methylprednisolone (corticosteroid) has been shown to be teratogenic in various animal species when given in doses equivalent to the human dose. There are no adequate and well-controlled studies in pregnant women. Methylprednisolone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal studies in which methylprednisolone has been given to pregnant rodents and rabbits have yielded an increased incidence of cleft palate in the offspring.

Infants born to mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Lactation: Methylprednisolone is excreted in breast milk. Caution should be exercised when methylprednisolone is administered to a nursing woman.

Adverse Reactions: Corticosteroids have a potential for multiple adverse effects. There are essentially 2 types of toxicity observed when administered in therapeutic dosages: withdrawal effects, which could produce life-threatening adrenal insufficiency; and high dosage over long periods, which could produce fluid/electrolyte disturbances, hyperglycemia, increased susceptibility to infections, peptic ulceration, osteoporosis, myopathy, behavioral disturbances, cataracts, or Cushing's habitus. Single doses, or short courses of therapy (over several days) usually have less harmful effects. The approach to therapy should follow logical and rational sequence of: (i) attempting to control the condition with more conventional mode(s) of management; (ii) weighing the benefits of steroid therapy against the risks; (iii) commencing therapy with a high loading dose, reducing to the minimum effective dosage as soon as possible.

Endocrine: menstrual irregularities; development of cushingoid state; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness; suppression of growth in children; decreased carbohydrate tolerance, manifestations of latent diabetes mellitus, increased requirements for insulin or oral hypoglycemic agents in diabetics.

The following additional reactions are related to parenteral corticosteroid therapy: anaphylactic reaction with or without circulatory collapse, cardiac arrest, bronchospasm, cardiac arrhythmias, hypotension or hypertension.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There is no clinical symptom of acute overdosage with this drug. Methylprednisolone is dialysable. The metabolism and excretion of methylprednisolone is similar to that of other corticosteroids. Continuous overdosage would require careful gradual reduction of dosage in order to prevent the occurrence of acute adrenal insufficiency.

For corticosteroids in general, anaphylactic and hypersensitivity reactions depending on their severity may be treated with antihistamines with or without epinephrine.

In the absence of specific rescue therapy, treatment is to be symptomatic and supportive.

Since injections of slightly soluble corticosteroids may produce atrophy at the site of injection, i.m. injections of these products should be made deeply into gluteal muscle; repeated i.m. injections at the same site should be avoided and these products should not be administered s.c.

Dosage And Administration: The minimum effective dosage should be sought once clinical control of the disease is obtained. Withdrawal should be slow and gradual in order to avoid glucocorticoid withdrawal syndrome.

Dosage ranges for corticosteroids are extremely wide and patient responses are quite variable. Dosage should be individualized according to the diagnosis, severity, prognosis, probable duration of disease, patient response and tolerance. For infants and children, the recommended dosage should be governed by the same considerations rather than by strict adherence to the ratio indicated by age or body weight.

As Adjunctive Therapy in Life-threatening Conditions (e.g., shock states): The recommended dose of methylprednisolone is 30 mg/kg, given i.v. over a period of at least 30 minutes. The large doses may be repeated every 4 to 6 hours for up to 48 hours.

Acute Spinal Cord Injury: For treatment of acute spinal cord injury, administer i.v. 30 mg methylprednisolone/kg of body weight in a bolus dose over a 15-minute period, followed by a 45-minute pause, and then a continuous infusion of 5.4 mg/kg/h for 23 hours. There should be a separate i.v. site for the infusion pump. The treatment should begin within 8 hours of injury.

Ulcerative Colitis: Methylprednisolone in doses of 40 to 120 mg administered as retention enemas or by continuous drip 3 to 7 times weekly for periods of 2 or more weeks has been shown to be a useful adjunct in the treatment of some patients with ulcerative colitis. Many patients can be controlled with 40 mg administered in 1 to 10 fluid ounces of water depending on the degree of involvement of the inflamed colonic mucosa. Other accepted therapeutic measures should, of course, be instituted.

In Other Indications: Initial dosage will vary from 10 to 500 mg depending on the clinical problem being treated. Larger doses may be required for short-term management of severe, acute conditions. Therapy may be initiated by administering methylprednisolone i.v. over a period of at least 5 minutes (e.g., doses up to 250 mg) to at least 30 minutes (e.g., doses greater than 250 mg). Subsequent doses may be given i.v. or i.m. at intervals dictated by the patient's response and clinical condition. Corticosteroid therapy is an adjunct to, and not replacement for, conventional therapy.

Methylprednisolone may be administered by i.v. or i.m. injection or by i.v. infusion, the preferred method for initial emergency use being i.v. injection. To administer i.v. (or i.m.) injection, prepare solution as directed (see Directions for Reconstitution).

The lowest possible dose of corticosteroid should be used to control the condition under treatment and, when reduction in dosage is possible, the reduction should be gradual.

Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Alternate day therapy (ADT) in which a single dose is administered every other morning is the dosage regimen of choice for long-term corticosteroid treatment.

Morning administration of the drug simulates the natural circadian rhythm of corticosteroid secretion which is high in the morning and low in the evening. This regimen provides relief of symptoms while minimizing adrenal suppression, cushingoid state, withdrawal symptoms and growth suppression in children. Intermediate acting agents should be used for alternate day therapy (see Table I).

Stability and Storage: Store intact vials at 15 to 25°C. Protect from light.

Reconstituted Solution: When reconstituted with Bacteriostatic Water for Injection, the resulting solution may be stored for up to 48 hours at 15 to 25°C. When reconstituted with Sterile Water for Injection, the resulting solution may be stored for up to 24 hours at 15 to 25°C due to risk of microbial contamination. The solution with a slight haze should be discarded. Discard unused portion.

Directions for Reconstitution: 1. Remove the protective plastic flip-top seal. 2. Swab the rubber stopper with an antiseptic solution and introduce the required quantity of the diluent by means of a syringe into the vial. 3. Shake the vial thoroughly to dissolve the powder content. 4. Withdraw the dose in the usual manner with the help of a syringe; unused portion should be discarded.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if solution is cloudy or contains a precipitate.

Preparation of Solutions for I.V. Infusion: First prepare the solution for injection as directed. Further dilution should be done immediately after reconstitution.

If desired, the medication may be administered in diluted solutions by admixing the reconstituted product with 0.9% Sodium Chloride Injection or with Dextrose 5% Injection. Concentrations of 1 mg/mL are physically and chemically stable for 24 hours at 15 to 25°C.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Compatibility: The compatibility and stability of methylprednisolone in solutions and with other drugs in i.v. admixtures is dependent on admixture pH, concentration, time, temperature, and ability of methylprednisolone to solubilize itself. Thus, to avoid compatibility and stability problems, whenever possible it is recommended that methylprednisolone for injection be administered separate from other drugs and as either i.v. push, through an i.v. medication chamber, or as an i.v. "piggy-back" solution.